Track: Formulation and Delivery - Chemical - Drug Delivery - Other Routes of Administration - Transdermal and Topical
Category: Poster Abstract
Physicochemical Properties of Poloxamer Gels Used to Improve Microneedle-Assisted Transdermal Delivery of Naltrexone
Purpose: The objective of this work is to determine the effect of naltrexone on gelation temperature of poloxamer formulations, with the goal of forming a drug depot in microneedle-treated skin. Naltrexone is a μ-opioid receptor antagonist used to treat alcohol and opioid dependence. Available routes of delivery include oral tablets and depot injections. The tablet shows considerable and variable first-pass metabolism while the injection requires frequent clinical visits. Transdermal delivery of naltrexone by means of microneedle (MN) patches could be a more patient-friendly alternative. MNs are small projections that painlessly form micropores in the stratum corneum, allowing hydrophilic drugs to cross the skin barrier more easily. Rapid healing of the micropores created by MN application limits the drug delivery time. Poloxamer gels could help extend the delivery time without compromising the natural skin healing process. Poloxamers are thermosensitive polymers that form gels at physiological temperature but are in a liquid state at lower temperatures. We hypothesize that cooled poloxamer solution will enter micropores formed by MNs and transition to a gel when warmed to skin temperature, forming an epidermal drug depot to continually release drug after the micropores close. We expect this to prolong total delivery time from one MN application. Methods: Naltrexone hydrochloride (NTX-HCl) permeation through MN-treated and intact porcine skin (dermatomed to 1 mm thickness) was measured using flow-through diffusion cells (0.64 cm2 diffusion area). In-plane MN arrays containing five metal projections (750 µm length) were applied to the skin twenty times to create 100 non-overlapping micropores. 700 µL of 110 mg/mL NTX-HCl in water solution was added to the donor reservoir and receiver solution was collected at 3h intervals for 24h. NTX-HCl concentration in each sample was measured using HPLC and the mean flux was calculated. The diffusion area was excised and NTX-HCl was extracted in methanol overnight to calculate the mass of NTX-HCl retained in the skin. Poloxamer 407 (P407) solutions in water were prepared under cold conditions (at 4 °C) to achieve 17, 18, and 19 wt% solutions. Solubility of NTX-HCl in the P407 solutions was determined by adding excess NTX-HCl and rotating overnight at 4 °C before centrifuging and analyzing using HPLC. The linear viscoelastic region of each P407 formulation was determined using amplitude sweeps on a rotational rheometer equipped with parallel plates and a solvent trap. Samples were heated to 37 °C after setting the geometry gap to 500µm. Strain was increased logarithmically from 0.01% to 100% and storage modulus (G’) was measured. The linear viscoelastic region was defined as the range of strain where G’ was constant. Gelation temperature of the P407 solutions was measured by performing temperature sweeps. The samples were heated to 14 °C and held at that temperature for five minutes to equilibrate. The temperature was increased by 0.5 °C and held at each temperature for one minute to equilibrate before G’ was measured until 37 °C was reached. Gelation temperature was defined as the temperature at which G’ plateaued. Effect of NTX-HCl on gelation temperature was analyzed by performing temperature sweeps on each of the P407 solutions with addition of 4.5 w/v% NTX-HCl. Results: Mean steady-state flux of NTX-HCl through MN-treated skin (440.7±8.7 µg/cm2-h) was almost two magnitudes higher than through intact skin (4.6±1.4 µg/cm2-h) with no apparent lag time under each condition. The mass of NTX-HCl retained in the skin after 24h was 4.3-fold higher for MN-treated skin (1.48±0.20 mg/g of skin) than intact skin (0.35±0.12 mg/g of skin). NTX-HCl solubility at 4°C in 17, 18, and 19 wt% P407 solution was 4.73±0.04, 4.78±0.02, and 4.57±0.05 w/v%, respectively. Therefore, 4.5 w/v% NTX-HCl was used for all P407 solutions. Viscoelastic properties were linear under 0.3% strain; therefore 0.2% strain was used for all experiments. Gelation temperatures were 27.25, 24.69, and 23.63 °C for 17, 18, and 19 wt% P407 gels (no NTX-HCl), respectively. Addition of 4.5 w/v% naltrexone to the 17, 18, and 19 wt% P407 solutions increased the gelation temperatures to 29.12, 26.62, and 24.64°C, respectively. Conclusion: NTX-HCl skin permeation is improved through MN treatment. All studied formulations formed a gel when heated to physiological skin temperature (32 °C). This shows promise for their applicability of forming a drug depot in MN-treated skin. Ongoing studies will quantify NTX-HCl release from P407 gels and permeation through MN-treated skin.